ABCA3 p.Pro193Arg
| Predicted by SNAP2: | A: N (66%), C: N (61%), D: N (61%), E: N (66%), F: D (59%), G: N (53%), H: N (66%), I: N (53%), K: N (66%), L: N (53%), M: N (57%), N: N (66%), Q: N (78%), R: N (66%), S: N (72%), T: N (78%), V: N (61%), W: D (71%), Y: N (53%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Ultrastructural and molecular analysis in fatal ne... Mod Pathol. 2007 Oct;20(10):1009-18. Epub 2007 Jul 27. Bruder E, Hofmeister J, Aslanidis C, Hammer J, Bubendorf L, Schmitz G, Rufle A, Buhrer C
Ultrastructural and molecular analysis in fatal neonatal interstitial pneumonia caused by a novel ABCA3 mutation.
Mod Pathol. 2007 Oct;20(10):1009-18. Epub 2007 Jul 27., [PMID:17660803]
Abstract [show]
Pulmonary surfactant is essential to maintain alveolar patency, and invariably fatal neonatal lung disease has been recognized to involve mutations in the genes encoding surfactant protein-B or ATP-binding cassette transporter family member ABCA3. The lipid transporter ABCA3 targets surfactant phospholipids to lamellar bodies that are lysosomal-derived organelles of alveolar type II cells. ABCA3-/- mice have grossly reduced surfactant phosphatidyl glycerol levels and die of respiratory failure soon after birth. We studied lung biopsy samples of two siblings with a novel homozygous ABCA3 mutation at nucleotide position 578 (c.578C>G), leading to a Pro193Arg amino-acid exchange, who died at 55 and 105 days of age. Light microscopy revealed thickened alveolar septa with abundant myxoid interstitial matrix, marked hyperplasia of type II pneumocytes, desquamation of alveolar macrophages and focal alveolar proteinosis. Surfactant protein-B was detected by immunohistochemistry after antigen retrieval. Transmission electron microscopy showed rare cytoplasmic inclusions with concentric membranes and eccentrically placed electron-dense aggregates. These 'fried-egg'-appearing lamellar bodies differed both from normal lamellar bodies and the larger, poorly formed composite bodies with multiple vesicular inclusions observed in surfactant protein-B deficiency. In conclusion, our findings underscore that the implications of interstitial lung disease in infant lungs differ from those in adults. In infants with a desquamative interstitial pneumonitis pattern, surfactant or ABCA3 mutations should be evaluated. Importantly, these findings support the notion that electron microscopy is useful in distinguishing between surfactant protein-B and ABCA3 deficiency, and has an important role in evaluating biopsies or autopsies of term infants with unexplained severe respiratory failure and interstitial lung disease.
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No. Sentence Comment
3 We studied lung biopsy samples of two siblings with a novel homozygous ABCA3 mutation at nucleotide position 578 (c.578C4G), leading to a Pro193Arg amino-acid exchange, who died at 55 and 105 days of age.
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ABCA3 p.Pro193Arg 17660803:3:138
status: NEW52 The patient was found to be homozygous for a point mutation of base pair 578 C4G in exon 7 (c.578C4G, numbering beginning at the ATG start as given in mRNA NM_001089.1), resulting in amino-acid exchange Pro193Arg (Figure 5).
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ABCA3 p.Pro193Arg 17660803:52:203
status: NEW96 The red circle indicates the novel mutation Pro193Arg found in this study, located in the first extracellular domain.
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ABCA3 p.Pro193Arg 17660803:96:44
status: NEW107 This ABCA3 mutation has not been described previously.8,10 Proline is known to have a strong structural effect due to its long side chain and is therefore also referred to as 'helix breaker`.33 As a consequence, the amino-acid exchange Pro193Arg implies an alteration of secondary molecule structure and is predicted to result in massive functional impairment of ABCA3.
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ABCA3 p.Pro193Arg 17660803:107:236
status: NEW109 The conventional and ultrastructural morphologic findings in our patients correlate with a severe phenotype associated with homozygous Pro193Arg ABCA3 gene mutation.
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ABCA3 p.Pro193Arg 17660803:109:135
status: NEW110 Absence of respiratory symptoms in the three Pro193Arg heterozygous adult patients implies sufficiently retained ABCA3 protein function in the heterozygous state.
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ABCA3 p.Pro193Arg 17660803:110:45
status: NEW